title: Soluble factors secreted by T cells promote β-cell proliferation.
abstract: Type 1 diabetes is characterized by infiltration of pancreatic islets with immune cells, leading to insulin deficiency. Although infiltrating immune cells are traditionally considered to negatively impact β-cells by promoting their death, their contribution to proliferation is not fully understood. Here we report that islets exhibiting insulitis also manifested proliferation of β-cells that positively correlated with the extent of lymphocyte infiltration. Adoptive transfer of diabetogenic CD4(+) and CD8(+) T cells, but not B cells, selectively promoted β-cell proliferation in vivo independent from the effects of blood glucose or circulating insulin or by modulating apoptosis. Complementary to our in vivo approach, coculture of diabetogenic CD4(+) and CD8(+) T cells with NOD.RAG1(-/-) islets in an in vitro transwell system led to a dose-dependent secretion of candidate cytokines/chemokines (interleukin-2 [IL-2], IL-6, IL-10, MIP-1α, and RANTES) that together enhanced β-cell proliferation. These data suggest that soluble factors secreted from T cells are potential therapeutic candidates to enhance β-cell proliferation in efforts to prevent and/or delay the onset of type 1 diabetes.
authors.affiliation: Section of Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center and Harvard Medical School, Boston, MA.
authors.forename: Ercument
authors.initials: E
authors.lastname: Dirice
authors.forename: Sevim
authors.initials: S
authors.lastname: Kahraman
authors.forename: Wenyu
authors.initials: W
authors.lastname: Jiang
authors.forename: Abdelfattah
authors.initials: A
authors.lastname: El Ouaamari
authors.forename: Dario F
authors.initials: DF
authors.lastname: De Jesus
authors.forename: Adrian K K
authors.initials: AK
authors.lastname: Teo
authors.forename: Jiang
authors.initials: J
authors.lastname: Hu
authors.forename: Dan
authors.initials: D
authors.lastname: Kawamori
authors.forename: Jason L
authors.initials: JL
authors.lastname: Gaglia
authors.forename: Diane
authors.initials: D
authors.lastname: Mathis
authors.forename: Rohit N
authors.initials: RN
authors.lastname: Kulkarni
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001786:Blood Glucose; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000166:cytology*; D007515:Islets of Langerhans / Q000166:cytology / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD
chemical_list: D001786:Blood Glucose; D016207:Cytokines; D007328:Insulin